Investigation into experimental toxicological properties of plant protection products having a potential link to Parkinson's disease and childhood leukaemia†

Abstract

In 2013, EFSA published a literature review on epidemiological studies linking exposure to pesticides and human health outcome. As a follow up, the EFSA Panel on Plant Protection Products and their residues (PPR Panel) was requested to investigate the plausible involvement of pesticide exposure as a risk factor for Parkinson's disease (PD) and childhood leukaemia (CHL). A systematic literature review on PD and CHL and mode of actions for pesticides was published by EFSA in 2016 and used as background documentation. The Panel used the Adverse Outcome Pathway (AOP) conceptual framework to define the biological plausibility in relation to epidemiological studies by means of identification of specific symptoms of the diseases as AO. The AOP combines multiple information and provides knowledge of biological pathways, highlights species differences and similarities, identifies research needs and supports regulatory decisions. In this context, the AOP approach could help in organising the available experimental knowledge to assess biological plausibility by describing the link between a molecular initiating event (MIE) and the AO through a series of biologically plausible and essential key events (KEs). As the AOP is chemically agnostic, tool chemical compounds were selected to empirically support the response and temporal concordance of the key event relationships (KERs). Three qualitative and one putative AOP were developed by the Panel using the results obtained. The Panel supports the use of the AOP framework to scientifically and transparently explore the biological plausibility of the association between pesticide exposure and human health outcomes, identify data gaps, define a tailored testing strategy and suggests an AOP's informed Integrated Approach for Testing and Assessment (IATA).

Guidance on harmonised methodologies for human health, animal health and ecological risk assessment of combined exposure to multiple chemicals

“…Strong associations were found and two relevant qualitative AOPs were developed. The PPR panel concluded that AOP-informed Integrated Approaches to Testing and Assessment (IATA) for parkinsonian motor symptoms can also be used to investigate such effects for binary mixtures of pesticides (EFSA PPR Panel, 2017) An important consideration in applying component-based approaches is whether and how to account for potential interactions between components. Interactions are defined as joint action between multiple chemicals that differ from dose addition or response addition categorised as less than additive (antagonism, inhibition, masking) or greater than additive' and are additive (synergism, potentiation).…”

Statement on the available outcomes of the human health assessment in the context of the pesticides peer review of the active substance chlorpyrifos

“…It was also noted that chlorpyrifos can produce DNA damage through topoisomerase II inhibition, as reported in one study using human foetal liver haematopoietic stem cells (Lu et al., ), which was mentioned in the EFSA Scientific Opinion on the ‘Investigation into experimental toxicological properties of plant protection products having a potential link to Parkinson's disease and childhood leukaemia’ (EFSA PPR Panel, ), but not evaluated in the RAR. Topoisomerase II inhibition is a mechanism likely to have a threshold (EFSA Scientific Committee, ); in addition, topoisomerase II inhibition may be involved as a molecular initiating event (MIE) for infant leukaemia (EFSA PPR Panel, ). All the experts agreed that a new Comet assay study might not be able to cover this concern.…”

“…Some experts also pointed out that epidemiological studies showed an important association between pesticides exposure and childhood leukaemia, including infant leukaemia (Ntzani et al., ; Hernández and Menéndez, ). It was noted that it is not possible to measure endpoints relevant for childhood leukaemia in current OECD standard Test Guidelines, due to higher sensitivity of haematopoietic stem and progenitor cells (HSPCs) compared to the standard cells, and the lack of exposure during the critical period (EFSA PPR Panel, ). This could be covered (in terms of exposure window, developmental period) by the extended one generation OECD 443 Test Guideline study (OECD, ), but the study is not designed for carcinogenicity assessment.…”

Neurotoxicity and underlying cellular changes of 21 mitochondrial respiratory chain inhibitors

“…Rotenone and MPP + , for which comprehensive studies were available, including mechanistic research and human data, have been used as main examples for AOP:3. On this basis, mechanistic plausibility could be demonstrated for epidemiological observations (Ockleford et al 2017). Notably, the AOP:3 has particular features on both ends: i) the binding of known inhibitors to cI (MIE) always leads to inhibition of the complex (Sherer et al 2007;Troger et al 2020).…”